Targeting IRAK1 as a Therapeutic Approach for Myelodysplastic Syndrome

Garrett W. Rhyasen, Lyndsey Bolanos, Jing Fang, Andres Jerez, Mark Wunderlich, Carmela Rigolino, Lesley Mathews, Marc Ferrer, Noel Southall, Rajarshi Guha, Jonathan Keller, Craig Thomas, LeviJ Beverly, Agostino Cortelezzi, Esther N. Oliva, Maria Cuzzola, Jaroslaw P. Maciejewski, James C. Mulloy, Daniel T. Starczynowski

Research output: Contribution to journalArticle

Abstract

Myelodysplastic syndromes (MDSs) arise from a defective hematopoietic stem/progenitor cell. Consequently, there is an urgent need to develop targeted therapies capable of eliminating the MDS-initiating clones. We identified that IRAK1, an immune-modulating kinase, is overexpressed and hyperactivated in MDSs. MDS clones treated with a small molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-κB inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is detrimental to MDS cells, while sparing normal CD34+ cells. Based on an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that cotreatment more effectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDSs.

Original languageEnglish
Pages (from-to)90-104
Number of pages15
JournalCancer Cell
Volume24
Issue number1
DOIs
Publication statusPublished - Jul 8 2013

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

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  • Cite this

    Rhyasen, G. W., Bolanos, L., Fang, J., Jerez, A., Wunderlich, M., Rigolino, C., Mathews, L., Ferrer, M., Southall, N., Guha, R., Keller, J., Thomas, C., Beverly, L., Cortelezzi, A., Oliva, E. N., Cuzzola, M., Maciejewski, J. P., Mulloy, J. C., & Starczynowski, D. T. (2013). Targeting IRAK1 as a Therapeutic Approach for Myelodysplastic Syndrome. Cancer Cell, 24(1), 90-104. https://doi.org/10.1016/j.ccr.2013.05.006